A hepatokine is a collective term for liver-derived secretory factors whose previously-unrecognized functions have been recently elucidated. We have rediscovered selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2) as hepatokines that are involved in the development of insulin resistance and hyperglycemia. The aim of this study was to determine whether and, if so, how oral glucose loading alters the two hepatokines in humans. We measured concentrations of serum SeP and plasma LECT2 during 75g oral glucose tolerance test (OGTT) (n=20) in people with various degrees of glucose tolerance. In OGTT, concentrations of both serum SeP and plasma LECT2 decreased at 120min compared with the baseline values, irrespective of the severity of glucose intolerance. Decrement of serum SeP during OGTT showed no correlations to the clinical parameters associated with insulin resistance or insulin secretion. In multiple stepwise regression analyses, plasma cortisol was selected as the variable to explain the changes in plasma concentrations of LECT2. The current data reveal the acute inhibitory actions of oral intake of glucose on circulating SeP and LECT2 in humans, irrespective of the severity of glucose intolerance. This study suggests that circulating SeP is regulated by the unknown clinical factors other than insulin and glucose during OGTT.